Oral treatment of seborrhea and compositions for use in said treatment

ABSTRACT

A method for treating a scalp characterized by an excessive secretion of sebum, to improve the condition thereof by reducing said excessive secretion comprising orally administering to a human being having a scalp so characterized a therapeutic composition comprising an ingestible carrier admixed with, as a non-toxic active compound, cysteine or cysteamine derivatives, the active compound is present in amounts of about 0.75-3 weight percent of the composition which is administered at a rate about 1-5 mg/kg/day based on the weight of the human being during a period of about 15 days.

United States Patent [191 Kalopissis et al.

ll ll 3,821,405 [4 1/ June 28, 1974 ORAL TREATMENT OF SEBORRHEA ANDCOMPOSITIONS FOR USE IN SAID TREATMENT [75] Inventors: GregoireKalopissis, Georges Manoussos, both of Paris, France [73] Assignee:LOreal, Paris, France [22] Filed: May 6, 1971 [21] Appl. No: 140,956

Related U.S. Application Data [63] Continuation-impart of Ser. No.706,652,Feb. l9, 1968, Pat. No. 3,629,452, Continuation-impart of S61.No. 801,154, Feb. 20, I969, abandoned.

OTHER PUBLICATIONS Stedmans Medical Dictionary, 21st Edition, p. 14329.6

1 Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Cushman,Darby & Cushman I [57] ABSTRACT A methodfor treating a scalpcharacterized byan excessive secretion of sebum, to improve thecondition thereof by reducing said excessive secretion comprising orallyadministering to a human, being having a scalp so characterized atherapeutic composition comprising an ingestible carrier admixed with,as a nontoxic active compound, cysteine or cysteamine derivatives, theactive compound is present in amounts of about 0.75-3 weight percent ofthe composition which is administered at a rate about l.5 mg/kg/daybased on the weight of the human being during a period of about 15 days-2 Claims, N0 Drawings atoms, glucosamine, NHNH NHOH,

1 ORAL TREATMENT OF SEBORRHEA AND COMPOSITIONS FOR USE IN SAID TREATMENTThis application is a continuation-in-part of our earlier applicationsSer. No. 706,652, filed Feb. 19, 1968,

now US. Pat. No. 3,629,452, and Ser. No. 801,154,

and the acid salts thereof,

wherein n is O or 1 and when n is O, R, and R are selected from thegroup consisting of hydrogen and CH 7 and when n is 1, R, and Rarehydrogen;

R is selected from the group consisting of hydrogen and COR1 wherein Ris selected from the group consisting of hydroxy, alkoxy containing 1-5carbon -O-CHr-H0Hi, N

, l i I wherein r' represents a member selected from the groupconsisting of hydrogen and alkyl having 1-3 carbon a g nsw -CONHe,nicotinoyl, g lutamyl, COR, and SOZR B wherein R is selected from the,group consisting of hydrogen. alkyl having l-18 carbon atoms, alkenylhaving 2-18 carbon atoms, A v V i OH on,

wherein P is 0-1 and R is selected from the group consisting ofhydrogen, alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms,halogen and acetamide, and wherein R is selectedfrom the groupconsisting of alkyl having 1-4 carbon atoms and wherein R has themeaning given above, t is 1 or 2 'and when t is 1, R is selected fromthe group consisting of linear or branched chain alkyl having 1-l8carbonatoms, alkenyl having 3-18 carbon atoms, propyne-Zyl, mono ordihydroxyalkyl containing 2-4 carbon atoms, l,2-dichlorovinyl,C(C8Hs)sr-(XCQQQ, CHKI H L,

, H'," (CH2)mO O f" wherein R l alkyl having 1-4 ca bon atoms and m atas-10g 1 1 wherein m is 1-2 and B is selected from the group iconsisting of -CH -CH and wherein R3 and A have hsmeal in ss ysnabgyo.cH2 ,-coR10 wherein s is 1-5 and-R 0 is selected from the groupconsisting of R piperidino, morpholino, pyrrolidino, N-methylpiperazinoand --N(CI-I2 CH OH)2, -'(CH ),-Re wherein z is 0, 1 or 2 and when 2 is0, R is selected from the group consisting of naphthyl-1 napthyl-2,pyridyl2, pyridy1-2 substituted with a member selected from the groupconsisting of nitro and alkyl having 1-4 carbon atoms, and pyridyl-Z-Noxide when R is hydrogen, and when 2 is 1, R is selected from the groupconsisting of naphthyl-l, naphthyl-Z, thienyl-2, tetrahydrofuryl-2,furyl-2, pyridy1-2, pyridy1- 2 substituted with a member selected fromthe group consisting of nitro and alkyl having 1-4 carbon atoms, andpyridyl-Z-N-oxide and when 2 is 2, R is selected from the groupconsisting of pyridlyl-Z, pyridyl-Z substituted with a member selectedfrom the group consisting of nitro and alkyl having 14 carbon atoms andpyridyl- 2-N-oxide, and e wherein x-is 0-2 and wherein when q is l, 2 or3,111,, is selected from the group consisting of hydrogen, halogen,alkoxy having 1-5 carbon atoms and linear or branched chain alkyl having1-4 carbon atoms, and when q is 1, R is selected from the groupconsisting of acetamido, amino, phcnoxy, cyclohexyl, mcthylenedioxy,trifluoromethyl, nitro, phenyl, dialkylamino wherein each alkyl moietyhas 1-5 carbon atoms, alkylthio having 1-5 carbon atoms, alkylsulfinylhaving 1-5 carbon atoms and alkyl-sulfonyl having 1-5 carbon atoms, andwhen t is 2, R is selected from the group 3 consisting of alkylenehaving 2-4 carbon atoms, alkylene having 2-4 carbon atoms andsubstituted with 1-2 hydroxy groups, butenylene and (CHz)z sOz HZlZUTaWhen the above active compounds contain at least one primary aminegroup, they are preferably used as salt with an inorganic or organicacid selected from the group consisting of hydrochloric, hydrobromic,sulfuric, phosphoric, p-toluene sulfonic, dihydrocinnamic, cinnamic,mandelic, salicylic, tropic, oxalic, malic, tartaric, succinic, acetic,lactic, 3-hydroxy butyric, fu-; maric, undecylenic, phenylacetic,monochloracetic, trichloroacetic, glycolic, nicotinic, p-aminobenzoic,glutamic, aspartic, citric, pentothenic, crotonic acid and ascorbic.

However, when the active compounds carry both an amine group and acarboxylic acid function it must be used in order to break the internalsalt an inorganic acid or a strong organic acid such asp-toluenesulfonic acid or trichloracetic acid.

In a related embodiment of the present invention the active compound isselected from the group consisting of a compounding having the formulaiR-S-CHz-CH-OOOR NHR wherein R is selected from the group consisting ofCOOR wherein n is 1-4, R is selected from'the group consisting ofhydrogen and CI-I and R is selected from the group consisting ofhydrogen and -COCH5;

2. the hydrochloride of the compound in (1) above;

3. a compound having the formula ll: H a-S O(C 2)nC 2-N wherein R and Rare each hydrogen; n is 0 or 1; R caresses #611221: htw sr rmisi d 92;.vrhsa2 0, R is selected from the group consisting of: (3 1-1-.-ctcaai.c. cinaia v.

5 g when p 1, R is selected of: CtHtQCQQBs which R5 =12rs .1t v hyd niwhen p 2, R is selected from the group consisting of: .9 5 9Rr. wh h R pes ts hydrogen,

-c HzNHq, -oH-.-NH,

R represents a member selected from the group consi tin c blQ F .."l!!QZQ n 4. the organic and inorganic acid salts of the compound in (3)above, said active compound being present in an amount ranging from 0.75to 3 percent, preferably 0.75 to 1.5 percent, by weight, of saidcomposition. 7

The organic or inorganic acids useful to prepare the active compound insalt form are hydrochloric, hydrobromic, salicylic, paratoluenesulfonic, citric, phosphoric, malic, tartaric, nicotinic and ascorbicacids.

v1n another related embodiment of the present invention, the activecompound has the formula wherein R is selected from the group consistingof alkyl, substituted alkyl, wherein the alkyl moiety has 1-18 carbonatoms, alkeny1 wherein the alkyl moiety has 3-18 carbon atoms, propyne-Zyl and mono and dihydroxy alkyl wherein the alkyl moiety is 2-4 carbonatoms and zls selected from the group consisting of hydrogen, -COR. andSO2R" wherein R is selected from thegroup consisting of lower alkylhaving l-6 carbon atoms, phenyl, benzyl and tolyl and R" is selectedfrom the group' consisting of lower alkyl having l-4 carbon atoms,phenyl, and tolyl, and the'nontoxic acidsalts thereof. Acids usefullyemployed to produce such salts include hydrochloric, phenylacetic,undecylenic and sorbic acids. I

The active compounds of this invention may be dissolved in a alimentaryliquid, such as an aqueous or hydro-alcoholic solution which may bearomatized.

They may also be incorporated into any injectable pharmaceuticalexcipient. They may then take, for example, the. form of granulas, pillsor tablets. Examples of such compoundings are described in the US. Pat.

The composition of this invention is administered at a rate of 1-5mg/kg/day based on the weight of the human being and is generallyadministered during a period of about 15 days. After 15 days, thetreatment may be stopped and then resumed 15 days later.

METHOD OF PREPARATION:

METHOD 1 The most commonly employed procedure is the substitutionreaction of essentially an equimolar ratio of a thiol with an organichalide or a methane sulfonate or a p-toluene sulfonate. The thiol can beaminated or not. The reaction is carried out under conditions generallyor conventionally employed for nucleophilic substitutions including, forinstance, a temperature ranging from to 100C. atmospheric pressure, andemploying a solvent such as water, ammonia, alcohol or dimethylformamide in the presence of a base such as an alkali or alkaline earthhydroxide, or carbonate, an alcoholate, an alkali or alkaline earthamide or even a tertiary aliphatic amine such as triethylamine according to the following general reaction:

The thiol R-SH or R'-SH can be prepared in situ by basic hydrolysis ofan isothiouronium salt according to the following general reaction:

METHOD I (alternative) When R is an aryl radical (X=O), the halide em-'ployed is an aryldiazonium halide (Vigneaud et al, J.Biol. Chem, 1941,138, 369 and Clarke and Inouye, J.Biol.Chem. 1931, 94.541) and thereaction follows the general equation:

The addition reaction of essentially an equimolarratio of a thiol with acompound having a reactive double bond is well known and can be carriedout, in accordance with known procedures, without a catalyst or in thepresence of a peroxide such as ascaridole, benzoyl peroxide, azobis-isobutyronitrile, or in the presence of a base such as thoseemployed in Method I, or even a quaternary ammonium hydroxide or asecondary amine such as piperidine. Representative reaction temperaturesinclude 10 to 100C and at atmospheric pressure, r

The reaction is most generally effected in a medium such as alcohol, forinstance, lower alkanol, water, dioxane, alone or in admixture, with abasiccatalyst, so as to obtain a small quantity of thiolate to initiatethe reaction.

The compound utilized having a reactive double bond does not have anamine function. It can, however, contain an amide or sulfonamidefunction.

The radical R can originate from either a compound having a reactivedouble bond (scheme 1) or from a thiol (scheme 2) when R and A are otherthan hydrogen.

SCHEME 1 SCHEME 2 fit; t n RSH (hp-NBA R--s-p pn :-nu R2 R3 R2 R3 (A andR3 are not hydrogen) METHOD lll .The compounds of the present invention,in which the sulfure atom is linked to a disubstituted or trisubstitutedcarbon atom, or to a benzyl or allyl radical, can conveniently beprepared at a temperature ranging from about 50 to 150C and atatmospheric pressure byreaction of essentially equimotar amounts of acorresponding tertiary or secondary, benzyl or allyl alcohol, with athiol, in the presence of a strong acid such as gaseous hydrochloricacid, p-toluene sulfonic acid. or a Lewis acid such as the etherate ofboron trifluo- R' and R"" only represent hydrogen when R represents arylor vinyl.

METHOD IV Another particularly useful method for preparing compounds ofthe present invention consists of reacting essentially equimolar amountsof a thiol with an ethylene imine or an acylation or N-sulfonylationderivative thereof at a temperature ranging from about-30 to C atambient or atmospheric pressures according to the following equationswhich provide an easy method of producing the following compounds:

The reaction is made very easily, in a variety of solvents, chosen as afunction of the solubility of the starting materials. Representativesolvents include alcohols of low molecular weight and chloroform.

METHOD IV (alternate) In addition to the above methods, the esters andthe amides of the present invention can be prepared starting with othercompounds.

Thus, esters can be obtained starting with the corresponding acide (ROH), by reacting an appropriate alcohol therewith to give the desiredester, either at an elevated temperature in the presence of a mineral orsulfonic acid, or at a low temperature in the presence of thionylchloride (Method V). v

' Amides included in the meaning of R can be prepared simply by thereaction of ammonia, hydrazine, hydroxylamine or an appropriate amine onthe ester noted above, at a temperature generally lower than 30C (MethodVI).

The amides included in A can be conveniently prepared by the action of ahalide or anhydride of a carboxylic acid to produce a carboxamide or bythe action of a sulfonyl halide to produce a sulfonamide when the amideis formamide, the-amide is prepared by action of formic acid. Thereaction conditions most generally utilized are those ofSchotten-Baumann, i.e., in water, in the presence of an alkalinehydroxide, or their rearrangement in an organic medium (aromatichydrocarbon, generally a chlorinated solvent) in the presence of a basesuch as pyridine or a tertiary amine, for example, trialkylamine (MethodVII).

When itis desired to prepare acylated compounds having an alcoholfunction, they can be obtained by the action of an amine on a lactone,the reaction being'catalyzed by an alkaline alcoholate.

In the case of substituted acetamides, acetylation of the amine canoften advantageously be effected by means of acetic anhydride in anacetic acid medium in the presence of concentrated sulfuric acid.

It will be noted, however, that the majority of the amides included inthe meaning 'of A are in addition easily produced by one or more ofMethods I-IV.

Finally, compounds of the type where A equals -CONH are prepared by theaction, in an aqueous or aqueous alcoholic medium, of an alkalinecyanate on a compound of the type A=I-I, in the presence of anequivalent amount of mineral acid, preferably, hydrochloric acid (MethodVIII), the starting compound being obtained according to Methods IIV.

The preparation of the salts of the active compounds is generallycarried out by first dissolving the acid in an appropriated solvent andthen pouring to this solution either a solution of the active compoundin the same solvent or the active compound alone. The solvent must notbe a solvent of the salt.

To prepare hydrochlorides, it is more convenient to dissolve the activecompound in an appropriated solvent and then to bubble in the solution aslight stream of hydrogen chloride.

REPRESENTATIVE EXAMPLES OF PREPARING ACTIVE COMPOUNDS ACCORDING TO THEFOREGOING GENERAL REACTIONS:

EXAMPLE 1 N-(Z-benzylthioethyl)nicotinamide: (Method VII) andcycioheiianefthere is recovered c olorles s crystals Y of the aboveproduct melting at 79C.

Analysis: S

Calculated,% Found,

10.3 ll.8 10.4 ll.9

' By bubbling I-ICl gas into an acetone solution of the above product,the hydrochloride thereof is recovered, which melts at 135C.

EXAMPLE 2 S-p-toluenesulfonamido 3-thia hexanedioic acid:

4 METHOD VII 17.9 grams of 3'-carboxymethylthio alanine are dissolved in200 cc of normal soda. There are added under agitation 24 grams ofp-toluene sulfonyl chloride then, in 3 hours, cc of normal soda. Thesuspension is agitated again for 5 hours at ambient temperature, thenfiltered. The filtrate, acidified with HCl, is extracted with ethylacetate. After evaporation of the ethyl ace- 9 tate, there remains ayellow solid which crystallizes in water. 20 grams of the above productin crystalline form are obtained having a melting point of 152C.

Analysis: C H S Calculated, 43.23 4.53 19.23 Found, 43.19 4.48 19.24

EXAMPLE 3 2-(2-p-toluenesulfonamido ethylthio) pyridine N- oxide (MethodVII) Analysisi Calculated, 8.64 19.77 Found, "/11 8.77 19.85

EXAMPLE 4 3-(2-pyridyl methylthio) alanine (Method 1) There are added,over a 15 minute period, 96 cc of N soda to an aqueous solution of 54 gof cysteine hydrochloride. The solution obtained is treated by a cat:

ion exchange resin and the product absorbed on the resin is liberatedwith an ammoniacal solution. The eluate. is evaporated and the residueis crystallized in a 'mixture of methanol and isopropyl ether. There isthus recovered 49 g of whitish crystals melting at 190C.

Analysis: N S

Calculated, 70 13.26 15.10 Found, 13.23 15.32

10 EXAMPLE .5

3-o-chlorobenzylthio alanine and the corresponding methyl ester (Method1).

In 400 cc of ethanol containing 6.9 g of sodium, there are introduced15.75 g of cysteine hydrochloride,.then a solution of 16 g ofo-chlorobenzyl chloride in 20 cc of ethanol. The mixture is heated for 1hour at 50C. After cooling, there are added 400 cc of water and 30 cc ofacetic acid. The product crystallizes and is filtered and washed withwater. Yield: 20.8 g. Fusion point is Analysis: C H N Calculated, 48.874.92 r 5.70 Found, 48.61 4.68 5.42

15 grams of the product obtained above are put into suspension in 15 ccof methanol, in which there is bubbled a stream of dry gaseous HCl for30 minutes. The reaction mixture is left standing for 2 hours at ambienttemperature, evaporated to dryness, the oily residue being dissolved in30 cc of methanol. The product is crystallized by the addition ofdiethyl oxide. Yield percent. Fusion point C.

There are heated under reflux for 30 minutes, 66.3 g of thiourea and145.6 g of B-bromoethylurea in 600 cc of isopropanol. The precipitate:g) is filtered,

washed with isopropanol and dissolved in 900 cc of water. There is addedto this solution during a 15 minute period, a solution of 30.45 g ofsoda in 150 cc of water and the resulting mixture is heated in a boilingwaterbath for 1 hour under nitrogen. The water bath is removed and thereis again introduced 159 cc of a-soda solution (30.45 g soda), then asolution of 127.15 g of fl-bromoethylurea in 150 cc of water.

The reaction mixture is left standing overnight at am bient temperature.The crystallizedproduct is then filtered, yielding 126 g of whiteproduct melting at 234C. Method VIII:

To a solution ol'92.4 g of2,2'thio diethylaminc in 70 cc of water. thereis added with agitation 133 cc of l 1.6 N hydrochloric acid whilecooling so as to maintain the temperature below about C. Then there isadded sufficiently rapidly, a solution of 127 g of potassium cyanate (98percent) in 150 cc of water. The reaction mixture is left standingovernight and the resulting pre- 1 cipitate is filtered, dried andcrystallized in water, yielding 128 g of white crystals, the fusionpoint of which is 234C.

Analysis:

Calculated, 7r Found, 7:

EXAMPLE 7 3,3(1,4 dithio butene-2diyl)dialanine (Method I) 2 There isobtained a yield of 97 percent ofa white solid.

Analysis: C H N Calculated, 7: 40.79 6.16 9.51 4 Found, "7( 40.74 6.239.23

EXAMPLE 8 3-,8-ureidoethylthio alanine (Method 1) 26.25 g of cysteinehydrochloride and 27.83 g of 6 B-bromoethylurea are dissolved in 150 ccof water under nitrogen. A solution of 13.35 g of soda in cc of water isadded during a minute period and the mixture is heated for 3 hours at C.After cooling, there is added to the solution, four times its volume of6 water and the resulting mixture is passed over a cation exchangeresin. After washing with water, the product fixed on the resin iseluted with an ammoniacal solution. The eluate is evaporated to drynessand the resi- LII Lil

. I, 12 due is crystallized in an aqueous methanol solution. There areobtained 19.5 grams of the white product melting at 220C withdecomposition.

Analysis: C H S Calculated. 34.80 6.28 15.46 Found. 7! 34.84 6.20 15.62

EXAMPLE 9 3-( 4-methoxycarbonylbutylthio)alanine hydrochloride(Method 1) Analysis:

Calculated. 11.85

Found. 7:

EXAMPLE 10 u 2-(5-methoxycarbonyl pentylthio)ethylamine hydrochloride(Method 1) CHJOCGZCHQS S' 4 CH2CH2NH2 HCl There are added successively,to a solution of 2.6 g of potassium in 100 cc of methanol, 4.5 goffi-mercaptoethylamine hydrochloride, then slowly 8.2 g of methylw-bromohexanoate.

The mixture is heated for 3 hours under reflux. After cooling, it isacidified with gaseous hydrochloric acid and filtered. The filtrate isevaporated to dryness and the oily residue (8 g) crystallizes rapidly.The product melts at C after crystallization in a mixture of methanoland diisopropyl oxide.

Analysis: Cl

Calculated. 7: Found. 7:

EXAMPLE 1 l alanine 13 14 D' HtCeH4--SOz-NH-OH2CH2O-SOr-Cb P-P- a Thissalt is dissolved in 25 cc of anhydrous dimcthyl +HSOH -CH-CO Hformamide and the'solution is cooled to -5C. Then 1 dropwise, whilemaintaining the temperature at 5C.

there is added a solution of 4.1 g of ethyl chloroforp-CH3CuI'I4-S02NHoH2oHzs-oH2-cl1H-o H mam H H The mixture is added dropwise to asolution of 25 g To a suspension of 17.55 g of cysteine hydrochlorideethyleneimine and 5 g of triethylamine in 50 cc otethyl monohydrate and37 gof 2-p-toluencsulfonamido ethyl acetate while maintaining thetemperature at SC. p-toluenc sulfonate in 500 cc of methanol, here isThe mixture is agitated for 20 minutes at -5C. added, during a one hourperiod, at 50C. a sol ion f 0 During a period of about minutes, there isadded 19.6 g of potassium at 85 percent in 500 cc of methaa filteredsolution of 6.6 g of cysteine hydrochloride and 4.2 g of triethylaminein cc of dimethyl forme potassium Chlor and Potassium P40111616 amide.After 30 minutes at 0C, the solution is filtered fonate are removed byfiltration. The mother liquor is d h filt i evaporated to dryness undera v p ra ed to dryness, leaving an oil which is mixe 5 uum. The oilyresidue is dissolved in ethyl ether and With water and acidified Withacetic acid. The product after tanding crystallizes in the form of awhite hygro precipitates and is crystallized in Watef- Yield is 29 gscopic product, the fusion point of which is 75-80C.

Fusion point is I percent EXAMPLE 12 The proportion of carboxylic acidand amine func- 20 trons correspond to theory.

2'-methylthioethylammonium phenylacetate EXAMPLE 14 (Method 1) 2- amino4-thia nonadioic acid (Methodll) v iB- 'T'QHATQHZINHQQZiCfQI 9 1 Y Thereare added, progressively and with intense agi- HO C CH CH $H+CH =CH (CHtation, 41 g of 2-bromo ethylamine hydrobromide to a l 7 solution ofsodium methanethiolate in ethanol (starting NH p with 9.6 g of methanethiol and 9.2 g sodium). A

The mixture is agitated for one hour at ambient tem- COZHQ H 'T I "S(CH2)4 z perature, then heated under reflux for minutes. 30 NH Aftercooling, the mixture is diluted with 200 cc of 2 ether and then filteredto remove therefrom the mineral salts. The filtrate is concentrated andthe resulting oily residue is fractionated. The fraction distilling at42C under 16 mm Hg, is recovered and yields 13.6 g (75 percent) -ofZ-methylthioethylanine which are added, in a solution of ether (300 cc),to a solution of phenyl-acetic acid (0.15 mol) in the same solvent. Thesalt formed crystallizes, in proportion to the addition, in the form ofwhite needles (33.5 g) which are purified by crystallization in ethylacetate. Yield 92 percent. Fusion point: 92-94C.

10 g of allylacetic acid are added dropwise to 15.75 g of cysteinehydrochloride. Under intense agitation. there are added 10 mg of benzoylperoxide. The mixture becomes heated and liquities and is maintained for1 hour at 80C. After cooling, it is dissolved in 50 cc of 2 N soda. Theprecipitate that forms is filtered and washed with water. Yield: 16.5 g.After crystallization in'dilute hydrochloric acid, the product melts at230C with decomposition.

The proportion of carboxylic acid function corresponds to theory.

EXAMPLE 15 Analysis, N i 5 45Bis[2-(2,2-dimethoxyethylthio)ethylamineloxalate (Method I) Calculated,7r 6.16 14.10 Found.'% an 14.01

011,0 I: CH-CHz-S-CHr-GHr-NHz1HOOC-COOH EXAMPLE l3 oHro A g 349,11dihydroxy 10,10-dimethyl 4,8-dioxo 3,7- diaza undecylthio)alanine-(Method IV) To a solution of 4.6 g of sodium in 150 cc of ethanol,

CH3 CH2 /CO2H HOCHr- CHOHPCO-NH-CHr-GHg-OO-i HSCHzOH H: CH2 NR2 CH: CO2HH0 0H,-i101-r0H-0o-NH-oHr-oH2-oo--NHoHz-oH2-s-oH2o 9H! V M 10 g ofcalcium pantothenate are dissolved in 10 cc there are added 1 1.35 g ofBmercaptoethylamine hyof water. To this solution are added, insuccession, 2.66 drochloride, the, dropwise 16.9 g of the bromide vof gof oxalic acid in a minimum of water and 10 cc of tri-'2,2'-dimethoxyethyl bromoacetaldehyde dimethylacethylamine. The calciumoxalate formed is removed by eta]- filtration. There is obtainedtriethylamine pantothenate in the form of an oil by concentrating thefiltrate to dry- The mixture is heated for 2 hours under reflux. The

ness. mineral saltsare filtered after cooling and the mother liquor isconcentrated. The oily residue is distilled in 17 mm Hg at l25130C.Yield 74 percent.

The 12.2 g of 2-(2,2-dimethoxyethylthio)ethylamine obtained above aredissolved in 50 cc of ethanol and added to a solution of 4.65 g of thedihydrate of oxalic acid. The salt formed crystallizes by addition ofethyl ether, after cooling. By crystallization in 2-propanol and ethylether, white crystals are obtained. Fusion point: 170l72C. Weight: 28.6g.

cc acetic acid there are added successively 15.42 g of p-methoxy phenyldimethyl carbinol and a solution of boron trifluoride in acetic acid.The mixture is heated 30 minutes at 60C, then cooled. This solution isadded dropwise to a 10 percent solution of sodium acetate, which isextracted three times with ethyl ether and dried over sodium sulfate. Bybubbling gaseous hydrochloric acid in the etherified solution, theproduct is produced as a white precipitate. Fusion point with decomposition: l72l74C. Yield: 62 percent.

To a solution of 6.9 g of sodium in 400 cc of absolute ethanol, thereare added, successively, 15.75 g of cysteine hydrochloride and 19.54 gof 2,4-dichloro benzyl chloride.

Then the mixture is heated at 50C for a period of 1 hour. By adding 600cc of water and 30 cc of acetic acid, the product crystallizes in theform of needles. Fusion point 205210C.

24.5 g of this product, 2-amino 3-(2,4-

dichlorobenzylthio) propionic acid, are acetylated in accordance withthe conventional Schatten-Baumann reaction. There is obtained aprecipitate which is crystallized in 40 percent ethanol, weight: 23.85g. Fusion point: 134-l35C.

Analysis:

Theory, 71 Found. 72

EXAMPLE 18 3-[ Bis-( P-methoxy A solution of 17.56 g of cysteinehydrochloride monohydrate in 85 cc of acetic acid is heated withagitation at 60C. Then there is added, successively, 24.4 g ofbis(p-methoxyphenyl)carbinoland 20.7 g of boron trifluoride in aceticacid. The mixture is heated at 80C for a period of 15 minutes, thencooled to 10C. Then.

by adding a solution of 48 g of sodium acetate in 50 cc of water and 150cc of ethanol. the product precipitates. After crystallization in amixture of water and dimethylformamide. there are obtained whitecrystals.

Analysis: c H N the fusion point of which is 209-21 1C. Yield: 85percent. Theory.% 55.05 7.70 5.35 Found. 54.98 7.85 5.21

Analysis: C H N EXAMPLE 17 Theory.% 62.22 (1.09 4.0

( '7 7') Z-acetamido 3-(2,4-dichlorobenzylthio)propionic Found 6 M5 acid(Methodl and V11) EXAMPLE 19 OHzCl NHCOCHa 2-allylthioethylammoniurnmalate CH2=CH-CH (Method I) H 24.2 g of allyl bromide are added dropwiseto a solution of 22.7 g of B-aminoethylthio'in 150 cc of ethanolcontaining 9.2 g of metallic sodium. The mixture is heated under refluxfor 1 hour. The resulting oil phase is decanted and dissolved by addingether thereto in order to eliminate by filtration the mineral salts. Thefiltrate is concentrated under vacuum, leaving an oily residue. Weight:38.1 g. The oily residue is dissolved in cc of absolute ethanol and 43.5g of malic acid are added with agitation in small portions. By addingether, the product forms as a white precipitate which, aftercrystallization in Z-propanol, melts at 94C. Yield: 65 percent.

Z-amino 4-[3-aminoethylthio butyric acid (Method 1) There are added, insmall amounts, 21.52 g of sodium to a suspension of 40 g of methioninein 1.5 l of liquid ammonia. After the addition, the mixture ismaintained under agitation for 4 hours. There is then added to theeluate provides a solid residue which is washed in ethanol and filtered.Yield: 62.5 g. Fusion point: 171C.

The proportion of acid and amine functions conform to theory.

18 EXAMPLE 22 S-B-ureidoethylmercaptoacetic acid (Methods 1 and VIII) Toa solution of 34.1 g of B-niercaptoethylamine a The solution is heatedat 50C for 2 hours while maintaining the pH at 6 by the addition of 2Nsoda. The mixture is then acidified, concentrated to dryness and washedwith a mixture of water and ethanol. After filtration, there is produced42 g of the product which melts at 135C.

mixture sufficient ammonium chloride to decolorize 25 t C H N S thesolution. The ammonia is evaporated overnight at Ca|cu|med 17, 3369 5,65I572 91, ambient temperature and the white residue is dissolved Found. 35.6 15.62 18.07 in 200 cc of water. There is added, over a 2-hourperiod, a solution of 55 g of 2-bromo ethylamine hydrobromide in 300 ccof water. The mixture is agitated for EXAMPLE 23 3 hours at 209C andthen for 3 hours at 50C. The reaction product is then treated with DOWEXResin 50 w, zfmethoxycarbonylmethylthloethylamme hydrochloand theneluted by means of an ammoniacal solution. (Method V) The eluate isconcentrated under vacuum. The solid CH3O CO CH2 CH2 CH2 NH2.HClres1due1s admixed with 75 cc of water, neutrallzed with y 52 cc of 6Nhydrochloric acid and treated with animal 135 g ofsl?-ammoethyl)mewaptoacenc acld and charcoal. There is obtained afterfiltration a colorless g of Propane are addedi solution which is thenconcentrated under .vacuum. F Y to a 501mm of g of hydroFhlor'c Thesolid residue is crystallized in a mixture of water, .acld m 20 cc ofmethanolgThe 9 permuted to methanol, acetone and is in the form of whitecrystals 40 stand for 12 hours at amb'em temperatur e- The flakes (38 g)melting at formed (17.5 g) are filtered and washed w1th ethyl acetate.Fusion point 100C.

Analysis CGHLSCINQOZS C H N HCl Analysis: Cl

Calculated. 7 33.66 7.03 13.05 17.03 Calculated)? 19.1 Found. 33.61 7.1813.08 17/08 Found, 7.

EXAMPLE 21 EXAMPLE M S-B-aminoethyl mercaptobutyric'acid (Method 1)N-(2-benzylth1oethyl)2,4-d1hydroxy 3,3-d1methyl 1 J 1 Mon butyramide(Method v11 :0 I s 2. BrcHacHzNHz-HBr CH3 0 r a H2NCH2CH2S CHgCHzOHzGQOH0H;- Asolution of 51 g of 2-thiolannone in 50 cc of methanol 1s added toa solutlon of 150 cc of 10 N soda, 400 0 cc of water and 500 cc ofmethanol. In the resulting so lution, there is introduced, in severalportions 103 g of B-bromoethylanme hydrobromide. The mixture 1s H heatedunder reflux for 3 hours. The solution is treated H t e with an ionexchange resin in hydrogen form, in accor- 13 g of pantolacetone with afew drops of a methanol dance with conventional procedures. Theconcentrated solution of sodium methylate are added to a solution of16.7 g 2-benzylthio ethylamine in 50 cc of ethanol. The mixture isheated for 6 hours at 60-65C.

After cooling, the product is crystallized by addition of diethyl oxide.White crystals (2.3.8 g) melt at C.

EXAMPLE 25 2-B-hydroxyethylthioethylamine (Method 1V) hydrochlorideCHr-CH HS CHr-CHzOH HOCHz-CHrS-CHPCHr-NH:

IHCI (gas) H CHr-OHz-S-CHr-CHrNHz-HCI There are added in 1 hour, 39 g of2 mercapto ethanol in 50 cc of ethanol to a solution of 21.5 g ofethyleneimine in 100 cc of ethanol. The mixture is maintained for 10hours at 40C and then concentrated to dryness. The oily residue (56 g)is fractioned under vacuum (1.5 mm Hg) and the fraction distilling atl13116C (48 g) is recovered.

By the action of gaseous hydrochloric acid on an ethanol solution of thedistilled amine, there is obtained the hydrochloride in the form ofcrystals (59 g) which melt at 45-48C. 7

Analysis: HCl

Calculated, 7: 23.15 Found. 7r 23.10

. EXAMPLE 26 3',3'-(2,2-sulfonyl diethylthio)dialanine and theN,N'-diacetyl derivative thereof. (Method 11 and VII) To a solution of70.2 g of cysteine hydrochloride monohydrate in 300 cc of water, thereis added, successively, 53 cc of 8 N soda, 0.5 cc of concentratedammonia and after 30 minutes, a solution of 23.6 g of divinyl sulfone in300 cc of water. After two hours under agitation, the reaction mixtureis filtered and the precipitate (67 g) is washed with water and withethanol.

Analysis: C H N Calculated. '7: 33.31 5.59 7.77 Found. 71 32.99 5.567.72

21.6 g of the precipitate obtained above are dissolved in 30 cc of waterand 150 cc of 8N soda. To this solution, there is added, successively,60 cc of acetic anhydride and 112.8 cc of 8Nsoda.

Agitation of the mixture is continued for some time and it is acidifiedwith 147.6 cc of ION hydrochloric acid. The precipitate formed infiltered and washed with water. Yield: 21.42 g. Fusion point: 196C.

Analysis: C H N Calculated. 7r 37.82 5.44 6.30 5.43 6.35

Found, 7: 37.38

EXAMPLES OF COMPOSITIONS AND THEIR USli IN ACCORDANCE WITH THISINVENTION EXAMPLES 27-34 The following composition is prepared and isusefully employed to reduce excessive secretion of sebum on the scalp.It is orally administered in the form of drops.

3-allyl thio alanine hydrochloride 1 g Glyccrine 40 g Ethyl alcohol 30 gWater. q.s.p. 100 g Lemon tincture (q.s.p. impart a pleasing aroma) Theoral administration of this composition at the rate of 10 drops each dayfor 15 days by a person having greasy hair due to excessive secretion ofsebum substantially improves the condition of the scalp and theappearance of the hair.

Essentially similar effective results are obtained when the 3-allyl thioalanine hydrochloride is replaced with the following compounds:B-(B-hydroxyethyl thio) alanine, 2-amino, 4-thia dodecanoic acid.2-(2-naphthyl thio) ethyl ammonium disuccinate, 2-(pyridyl-2-methylthio) ethylamine dihydrochloride, Z-cetylthio ethylamine hydrochloride,2-(3,4-dimethoxy benzylthio ethylammonium malate and 2-amino4-tetradecylthio butyric acid.

EXAMPLES -41 The following composition is prepared: 35

3-methylthio alanine hydrochloride mg Glucose 300 mg Water. q.s.p. 5 mlOrange juice (q.s.p. to impart a pleasant aroma) EXAMPLE 42-48 Lozengesfor oral consumption having the following composition are prepared:

3-(B-ureidoethylthio)alanine 6O 20 mg Lactose 300 mg Powdered gum arable100 mg Simple syrup. q.s.p. 500 mg These lozenges, taken at a rate of 15each day, by a person having greasy hair and scalp due to excessivesecretion of sebum substantially improves the condition of the scalp andthe appearance of the hair by reus nseiss vs sssrst gn stssbum-mEssentially similar effective results are achieved'by replacing the3-(B-ureidoethylthio)alanine by the following compounds: 3-octylthioalanine, 2-(3,4 methylenedioxybenzylthio)ethylamine hydrochloride, 3-(2-22 EXAMPLES 5456 Tablets the following composition are prepared:

pyridyl N-oxide methylthio)alanine, o-flaorobenzylthioethylammehydrochloride, 2-amino s p wluencsulfonamido 34m4-(o-chlorobenzylth1o)methyl butyrate hydrochloride, hexane dioicacid1.0 mg and 6-amino 3-thia dimethyl heptanedioate hydrochlomg Gum arabic100 mg lldE. Starch, q.s.p. 500 mg EXAMPLES 49-53 These tablets taken ata rate of 10 each day for 20 Chewable pellets having the followingcomposition days by a person having greasy hair and scalp because areprepared: of excessive secretion of sebum effectively reduces excessivesebum secretion and significantly improves the 3 2 Id 1 h 1h 1 2 Sappearance of the hair and scalp condition. j y l t 6 2 Essentiallysimilar effective results are achieved Lemon syrup 50 g whenS-p-toluenesulfonamido 3-thia hexane dioic acid v is replaced by thefollowing compounds: 2,4-dichloro These pellets, administered at therate of a coffee Z-benzyl thio ethylamine aspartate and N-[2-( 3,5dispoonful twice a day to a person having greasy hair and chlorobenzylthio) ethyl] trifluor o acetamide. scalp due to excessivesecretion of sebum substantially Table I below lists active compoundswhich are cystereduces excessive secretion of sebum and thereby siginederivatives and which are usefully employed in the nificantly improvesthe condition of the scalp and the present invention. Table l identifiesthe general method appearance of the hair. i by which the activecompounds are prepared in accor- Essentially similareffective resultsare achieved by dance with methods l-VIII, above, as well as represenreplacing 3-(2-pyridyl methylthio)alanine by the foltative compositionsin which they are included for oral lowing compounds: 6-amino 3-thiaheptanedioic acid, administration to humans having a scalp characterized.2-(undecenyl thio)ethylamine, 3-methylthio 2- by excessive secretion ofsebum, to reduce said excespropionamide dimethyl amino ethyl propionateand 3- sive secretion so as to improve the condition of the benzylthioZ-butyramido propionic acid. scalp and to improve the appearance of thehair.

. T LE I No. Active Compound Method of Form of Amount in PreparationComposition Composition 1 3-methylthio alanine l Drops as in .75 g

Ex.2734. 2 3'methylthio alanine hydrochloride 1 do. .75 3S-isopropylthio alanine l or 111 do. .75 4 3-n-octylthio alanine 1 do..75 5 3-(2-ethyl hexylthi0)alanine 1 do. .75 6 3dodecylthio alanine 1do. 1.00 7 3hexadecylthio alanine 1 do. 1.00 8 3-octadecy1thio alanine I1 do. 1.00 s 9 '3-(9-octadecene-ylthio) alanine 1 do. 1.00 l03-allylthio alanine 1 do, 1.00 1.1 3-allylthio alanine hydrochloride 1do. [.25 12 3-(2-butene-ylthio)alanine I do. 1.25- 13 1.2-dichloro3-vinylthio alanine I do. 1.25 l4 3-(2-propyne-ylthio)alanine 1 do. 1.2515 3-t-buty1thio alanine 111 do. 1.25 16 3.3-(2-butene1,4-diyl-dithio)dialanine I do. 1.50 17 Ii-flhydroxyethylthio alanine lor lV(alternative) do. 1.50 18 3-(-2.3-dihydroxy.propylthimalaninelV(alternative) do. 1.50 g 19 3-(2-hydroxy propylthio) alaninelV(alternative) do. 1.50 20 3-(2,2-(dimethoxy ethylthio)alanine I do.1.50 21 3-(3.3-dieth0xy propylthio)alanine 1 or 11 do. 2.00 22 3-(1,2-propylcnedioxy ethylthio)alanine I do. 2.00 23 342,2-ethylenedioxypr0pylthio)alanine 1 or 11 do. 2.00 24 3-l3-ureiodethylthio alanine 1do. 2.00 25 3-,8-acetamidoethylthio alanine 1 or IV do. 2.00 26Z-Bp-toluenesulfonamido B-ethylthio alanine 1 or N do. 2.50 27Il-B-phenylacetamidoethylthio alanine I -do. 2.50 28 3 fiaminoethylthioalanine I or IV do. 2.50 29 3-B-nicotinamidoethylthio alanine l or IVdo. 3.00 30 3-[2-(2.4-dihydroxy 3.3-dimethyl butyramido) cthylthio]alanine Vll do. 300 31 3-19.11-dihydroxy 10.10-dimethyl 4.8-dioxo3.7-diaza undccylthiolalanine IV do. 300 32 3.3"thio dialanine [I do.3.00 33 3-(w-amino w-carboxypropylthio) alanine l or 11 do. 3.00 34S-(3-ulanyl) Nacetyl cysteine l1 Ampoules as in Ex. 35-41 0 mg 35 13(2-naphthyl l or 11 do. 50 mg thio) alanine 36 S.S-[2,3-dihydroxy1.4-butanediyl] bis cysteine 1 do. 50 mg 37 3-(2-thenylthio) alanine Ido. 50 mg 38 3-ochlorobenzylthio alanine 1 do. 50 mg 393-p-chlorobenzylthio alanine 1 do. 50 mg 40 3-furfurylthio alapine 1 do.mg

' TABLE i nue No Active Compound Method of Form of Amount in PreparationComposition Composition 41 3-tctrahydrofurfurylthio alanine 1 do. 50 mg42 3-(2-pyridyl methylthio) alanine I do. 50 mg 43 3-B-phenylethylthioalanine 1 or 11 do. 50 mg 44 3-(2-pyridyl thio) alanine 1 do. 50 mg 453-diphenylmethylthio alanine 111 (and 1) do. mg 46 3-(2-pyridylethylthio) alanine 11 or 1 do. 50 mg 47 3-(2,4-dichl0r0 benzylthio)alanine 1 do 50 mg 48 3-(3.4-dichloro benzylthio) alanine 1 do 50 mg 493-(3,5-dichloro benzylthio) alanine 1 do 50 mg 50 3-(2,6-dich1orobenzylthio) alanine 1 do 50 mg 51 3-o-methoxybenzy1lhio alanine 1 d0 50mg 52 3-p-butoxybenzylthio alanine 1 do. 50 mg 53 3-p-methoxybenzylthioalanine 1 do. 50 mg 54 3-p bromobenzylthio alanine 1. do. 50 mg 553-m-fluorobenzylthio alanine 1 do. 50 mg 56 3-(3,4-dimethoxybenzylthio)alanine 1 do 50 mg 57 3-(3,4-methylenedioxy benzylthiohlanine1 do 50 mg 58 3-p-fluorobenzyllhio alanine 1 do. 50 mg 593(3,4,5-lrimcthoxy benzylthio)alanine l do. 50 mg 60 3-(2-pyridylN-oxide methylthio)alanine 1. do. 50 mg 61 3-o-mezhylbenzylthio alanine1 do. 50 mg 62 B-p-melhylbenzylihio alanine 1 do 50 mg 63 3-(4-t-bulylbenzylthio)alanine l do 50 mg 64 3-o-flu0robenzylthio alanine l do 50 mg65 3-(4-isopropyl benzylthio) alanine 1 do. 50 mg 66 3-(2.4-dimethylbenzylthio) alanine 1 Lozenges as 10 mg in Ex. 42-48 673-p-trifluoromethyl benzylthio alanine 1 do. 10 mg 683-o-trifluoromethyl benzylthio alanine 1 do. 10.00 mg 69Lp-acetamidobenzylthio alanine 1 do. 10.00 70S-p-dimethylamino-benzylthio alanine 1 do. 1000 71 3-p-phenoxybenzylthioalanine 1 do. 15.00 72 3-p-phenylbenzylthio alanine 1 do. 15.00 733-(4-methylthio benzyllhio)alanine 1 do. 15.00 74 3-(4-propylsulfonylbenzylthio)alanii1e 1 do. 15.00 75 3-(4-butylsulfonyl benzyllhio)alanine1 do. 15.00 76 3-(2-me1hylthio benzylthio)alanine 1 do. 15.00 773-benzyllhio alanine 1 do. 17.50 78 Z-amino 3-benzylthio propionamidehydrochloride Vl d0. 17 50 79 3-benzylthio 2-nicotinamido propionate ofZ-hydroky 2-pr0pyl V or Vll do. 17.50 80 3-benzylthio 2-nicotinamidopropionic acid V11 do. 17.50 '81 3-eth0xycarbonyl methylthio alaninateof ethyl V do. 17.50 82 5-p-toluene sulfonamido 3-!hia hcxanedioic acidV11 do. 8.00 83 S-p-acetamidobcnzene sulfonamido Bahia hcxancdioic acidV11 do. 8.00 84 2-propionamido 3-thia hexanedioic acid V11 do. 8.00 852p-acetamidobenzamido 3-benzyllhio V11 do. 8.00

propionic acid 86 2-methanesulfonamido 3-dodecyllhio V11 do. 8.00

propionic acid 87 S-bcnzamido 3-thia hexanedioic acid V11 do. 8.00 88Z-glutamino 3-methylthio propionic acid V11 do. 8.00 89 S-ureido 3-thiahexanedioic acid Vlll do. 8.00 90 N-(Z-amino Lbcnzylthio propionyl)glucosamine hydrochloride VI do. 8.00 91 2-formamido 4-ihia heplanedioicacid V11 do. 8.00 92 3-bcnzylthio 2-'(9-octadecene amide) propionic acidV11 do. 8.00 93 2-amino 3-benzylthio propionhydroxamic V1 do. 15.0

acid 94 Z-acelamido 3-benzy1thio propionhydrazide V1 do. 15.0 952-propionamido 3-bcnzylthio propio'nhydroxamic acid V1 do. 15.0 963-p-ethoxy benzylthio alanine 1 do. 15.0 97bis-(p-methoxyphenyl)3-meihylthio alanine l or 111 do. 15 0 Chewable 983-(2-p-methoxyphenyl 2-propyl thio) pellets as alanine l or 111 in Ex.49-53 1.90 g 99 3-(2-naphthy1 methylthio)alanine 1 do. 1.90 g 1003-phenylthio alanine 1(alternative) or 11 do. 190 g- 101 3-0, m orp-chlorophenylthio alanine 1(a1ternative) or 11 do. 1.90 g 102S-p-fluorophenylthio alanine 1(alternative) or 11 do. 1.90 g 103 3-o orpmethoxyphenylthio alanine v 1(a1ternative) or 11 do. 1.90 g 1043-benzylthio valine 11 do. 2.5 g 105 2-amin0 4-benzylthio bulyric acid 1do. 2.5 g 106 3-carbamyl mcthylthio alanine 1 do. 205 g 107S-yaminopropylthio alanine 1 do. 2.5 g 108 3-o-aminophenylthi0 alanine 1do. 2.5 g 109 3-(2-carb0xy ethyllhio)alanine 11 or 1 do. 2.5 g 1 10B-B-buioxy carbonyl elhylthio alanine 11 do. 3.75 g l l l 3-propoxycarbonylmethylthio alanine V do. 3.75 g 1 l2 3-w-melhoxycarbonylbutylthio alanine 1 do. 3.75 g 113 3-m-methoxy carbonyl pcnlylthioalanine 1 do. 3.75 g 114 3-(3-carboxy propylthimalanine 1 do. 3.75 g 1l5 Z-amino 4-1hia nonanedioic acid 11 do. 50 g 1 l6 2-amino 4-thiadecanedioic acid 1 do. 5.0 g

TABLE I-Qontmued No Active Compound Method of For of Amount in i m Prepration Composition Composition I I7 Z-amino 4-thia dodecanedioic acid Ido. g l 18 3-carboxymethylthio alanine. I do. 5.0 g l 19 N(2-acetamido3-benzylthio propionyl) glucosamine Vl do. 5,0 g I20 3-benzylthio 2-(lO-undecene-amido) propionic acid Vll do. 5.0 g 12] 3benzylthioZ-octadecanamido propionic acid Vll do. 6.25 g 122 3-carhamylthioalanine Vlll do. 6.25 g 123 3-mcthylthio Z- ropionamido propionatc ol'dimcthylaminocthyl V do. 6.25 g I24 Z-acctamido 3-benzylthio propionateof dicthylaminoethyl V do. 6 5 g 125 3'benzylthio Z-propionamidopropionatc of l-butoxy 2-propanol V do. 750 g 126 S-amino 3-thiahexanedioate of di ([3'pipcridin0ethyl) hydrochloride V do. 50 g [273.3-(2.2-sult"onyl diethylthio)dialanine ll do. 7 50 g 1283-onitrophenylthio alanine I do. 50 g Tablets as 1293B'piperidinocarhonyl ethylthio alanine l or II in Ex. 54-56 6 mg [30'l-acetamido 3-pyrrolidinocarbonylmcthylthio propionic acid I do. 6 mg[31 2 amino 4-ortho-chlorobenzylthio butyratc of methyl hydrochloride Ido. 6 mg 132 Z-amino 4-B-amino ethylthio butyric acid hydrochloride Ido. 6 mg [33 2-propionamido 4-tetradecylthio butyric acid .Vll do. 6 mg[34 Z'amino 4-tetradecylthio butyric acid I do. 6 mg I35 fi-amino 3-thiaheptanedioic acid I do. 6 mg 136 S.S'-(2 butenel.4-diyl)bis-homocysteine I do. 6 mg 137 N-formyl S-methyl penicillaminelor. Vll do. 6 mg 138 Z-amino 4thia heptanedioic acid ll or I do. 7.5 mg139 S-carboxymethyl cysteinate of methyl Vll do. 7.5 mg 140S-nicotinamido 3-thia hexanedioic acid Vll do. 7.5 mg 14]5-p-acetamidobenzamido 3-thia hexanedioic acid Vll do. 7.5 mg 142S-p-butoxybenzamido 3-thia hexanedioic acid Vll do. 7.5 mg 1435-dodecanamido 3-thia hexanedioic acid Vll do. 7.5 mg I44 fi-amino3-thia heptanedi'oate of dimethyl V do. 7.50 mg 145 5-p'methoxybenzamido3-thia hexanedioic r acid r Vll do. 750 mg I46 Z-ucetamido 4-thianonancdioicacid Vll do. 7.50 mg 147 3-benzylthio 2-butyramido propionicacid Vll do. 7.50 mg I48 3-benzylthio Z-propionamido propionic acid Vlldo. 7.50 mg I49 J-benzylthio 2-methanesulfonamido propionic acid Vll do7.50 mg 150 3benzylthio Z-ethanesulfonamido propionic acid Vll do.It).() mg l5] S-benzylthio Z-propanesulfonamido propionic acid Vll do.It).() mg I52 3-henzylthio 2-hutancsult'onamido propionic acid Vll do.HUI mg I53 Z-acclamido J-henzylthio propionic acid Vll do. HM) mg I54Z-amino 3-heuzhydryl propionate of methyl hydrochloride V do. [0.0 mgS-acctamido 3-thia hcxanedioic acid Vll do. HM) mg 156 S-(carboxymethyl)cysteinate ol hutyl I do. l2. mg 157 S-(ethoxy carbonyl methyl) cysteinel and V do. I25 mg l58 S-propoxy carbonyl methyl) cysteine l and V do.l2. mg 159 S-(butoxy carbonyl methyl) cysteine land V do. 12. mg 160S-(methoxy carbonyl ethyl) cysteine ll do. 150 mg 16] S (methoxycarbonyl propyl) cysteine l and V do 15.0 mg l62 S-(methoxy carbonylbutyl) cysteine l and V do. l5.0 mg l63 3-(l-naphtyl Z-methylthio)alanine l do. l5 mg Table II, below. lists active compounds which are 55cysteamine derivatives and which are usefully employed in the presentinvention. Table I1 identifies the general method by which the activecompounds are prepared in accordance with Methods I-VIII disclosedhereinbefore, as well as representative compositions in 60 which theyare included for oral administration to humans having a scalpcharacterized by excessive secretion of sebum to reduce said excessivesecretion so as to improve the condition of the scalp and to improve theappearance of the hair.

TABLE II No. Active Compound Method of Form of Amount in PreparationComposition Composition 1 Z-methylthio ethylaminc (cinnamate) I or IVDrops us in 0.75 g

Ex. 27-54 2 Z-mcthyl thio ethylurcu l or VIII do. 0.75 3 N-(2 mcthylthioethyl) p-acetamido bcnzztmidc VII. IV or 1 do 0.75 g 4 N(2-mcthylthiocthyI)p-acctamido benzencsulfonamide VII, IV or I do. 0.75 g 5N-(2-propylthioethyl)-p-mcthoxy benzamidc VII, IV or I do. 075 g 6N-(butylthio ethyl) nicotinamide I or VII do. 1.0 g 7 N-(Z-dodecylthioethyl) p-butoxybenzamide VII or IV do. 1.0 g 8 N-(Z-methylthio ethyl)p-toluenesulfonumide VII or IV do 140 g 9 N (2-isopropy1thio ethyl)propionamide VII or IV do. 1.0 g 10 N-(Z-octylthio ethyl) acetamidc VIIor IV do. 1.0 g I l N-(2-butylthio ethyl) methanesulfonumidc VII or IVdo. 1.0 g 12 N-(2-isopcntylthi0 eIhyUbutane sulfonamide VII or IV do.125 g 13 his 1.4(2-acctamid0 cthylthio) 2.3-butanediol I or IV do. 1.25g 14 Z-hexudccylthio cthylamine hydrochloride I or IV do. v 1.25 g 162-allylthio cthylaminc mulutc 1 Drops as in 1.25

- Ex. 27-34 17 9-octzideccnc 2-ylthio cthylumine hydrochloridc I do.1.25 g 18 Z-dodccylthio cthyluminc hydrochloride 1 or IV do. 1.25 g I)lisopuniylthio clhylztminc mnndclzitc I or IV do. 1.25 g 21)loclndccyllhio cthyluminc sulit'ylulc l or IV do. 1.511 g 21Z-fl-hydroxycthyl thio cthylurczi I or VIII do. 1.50 g 22 2fi-hydroxycthylthio cthylatminc hydrochloride 1 or IV do. 1.50 g 232-(2,3-dihydroxy propylthio)cthyluminc p-tolucnesultonutc l or IV do. 151) g i 24 2-(2hydroxy propylthiolcthylumine oxalate IV do. 1.50 g 25N-(2-mcthylthio ethyllphenylacetumide VII do. 1.50 g 26 2-(2.2-dimethoxyethylthio) cthyluminc I hydrochloride I do. 1.50 g 27 2-(2,2-dimethoxyethylthio) ethylumine undecylenate I do. 2.0 g 28 2-(2.2-diethoxyethylthio) ethylamine undecylenate l y do. 2.0 g 29 2-(2,2-diethoxyethylthio)ethy1amine acetate 1 do. 2.0 g 30 Z-undecenylthio ethylamine 1do. 2.0 g 31 Z-B-ureidoethylthio ethylamine hydrochloride 1 or IV do.2.50 g 32 2-fi acetumidoethylthio cthylamine tropate I or IV do. 2.50 g33 2,2'-thio diethyluminefumaratc 1 or IV do. 30 g 34 2.2'-thiodiethylurea VIII or 1 Ampoulcs as in Ex. 35-41 50 mg 353-fi-amin0cthylthio propylaminc hydrochloride 1 or IV do. 50 mg 36S-B-urcidocthyl thiocurbumtttc VIII do. 50 mg 37 Z-cthoxycarhonylthiocthyluminc hydrochloride I do. 50 mg 38 2-dimethylzimino curbonylthiocthyluminc sulfate 1 do. 51) mg 39 Z-butoxycurbonyl mcthylthio cthylurcal or IV do. 50 mg 40 2-cthy1oxycarbonylmethylthio ethyluminchydrochloride V do. 50 mg 41 6-B-uminoethylthio hcxanoutc of methylhydrochloride 1 do. 51) mg 42 S-B-uminoothylthio pentunoic acid 11 do.50 mg 43 2-phcnylthio cthyluminc dihydrogcn phosphate 1 or IV do. 50 mg44 2-p-t-buty1pheny1thio ethyluminc trichlorzicetate l or IV do. 50 mg45 2-p-methoxyphenylthio cthylumine ditartrutc I or IV do. mg 462-toly1thio ethylamine hydrobromidc I or IV do. 50 mg 47 2-(1biphenylthio) ethylumine hydrochloride 1 or IV do. 50 mg 482-N-penttichIorophenylthio ethyl I acctumide I or IV do. 50 mg 492-benzylthio ethylumine malute I or IV do. 50 mg 50 Z-benzylthioethylamine nicotinute l or IV do. 50 mg 51 2-bcnzylthio Z-methylpropylumine hydrochloride 1 do. 50 mg 52 2-bcnzylthio propyluminelactate I do. 50 mg 53 N-(Lbenzylthio ethyl )nicotimtmidc Ihydrochloride: VI do. 50 mg 54 N-(2-bcnzylthio ethyl) IO-undeccnc amideV11 or IV do. 50 mg 55 N-(2-hcn7.ylthi0 cthyl) hcxadecunumidc V11 or IVdo. 51) mg, 56 S-B-uminocthyl nicrcaiptobutyric acid I do. 50 mg 57N-(Z-hcnzylthio cthyl)formiimidc VIl do. 50 mg 511 N (2-hcn1.ylthioethyl)phcnylucutzimidc Vll or IV do. 50 mg 5) N-l2-(2.(\-tlll11 .1ll1)'lphcnyllcthyl] hcxunumide Vll or IV do. .50 mg (10 Z-o-uminophcnylthiocthyluminc succinntc or IV do. 50 mg 61 N-(2bcnzylthio ethyl) glulzimincVII do. 50 mg 62 Sfi-hminoethyl mcrcupto acetic acid I do. 50 mg (\3(IlS-B-uminocthyll mcrcupto propionic acid 7 11 do. 50 mg 64(3-S-y-annino propyl) mcrcupto acetic acid I do. 511 mg 65S(2qvmcthoxyhcnzmnido cthyll mcrcapto Lozenges as acetic acid l in Ex.4248 7.111) mg ABLlin LiQtmi lui,

No. Active Compound Method of Form of Amount in Preparation CompositionComposition 1 17 3-(2.2'-dimethoxy ethylthiolprop ylamine sulfate Vll orIV do. g l 18 S-fi-aminoethylmercapto acetic acid Vll or IV do. 5.0 g 119 The hydrochloride of S-B-aminoethyl mercapto acetic acid VII or IVdo. (1.25 g N-(Z-bcnzylthioethyl)acetamide Vll or IV do. 6.25 g 121N-(Z-benzylthioethyl)propionamide Vll or IV do. (1.25 g 122N-(2-benzylthioethyl)butyramide Vll or IV do. (1.25 g 123N-(2-benzylthioethyl)methanesulfonamide Vll or IV do. 6.25 g 124N-(2-benzylthioethyl)ethanesulfonamide Vll or IV do. 6.25 g 125N-(2-benzylthioethyl-propanesulfonamide Vll or IV do. 750 g 126 N(Z-benzylthioethyl)butanesulfonamide VII or IV do. 7.50 g 127S-(Z-p-acetamidobenzenesulfonamido ethyl) mercapto acetic acid I or IVdo. 7.50 g 128 S-(Z-p-acetamidobcnzamido ethyl) mercapto acetic acid Ior IV do. 7.50 g 129 N-( 2-thenylthioethyl)acetamide VII or I do. 7.50 g130 2-benzylthio propylamine I do. 7.50 g 131 Z-henzylthio Z-methylpropylamine I Tablets as in Ex. 54-56 6 mg 132Z-(Z-p-toluenesull'onamido ethylthio) pyridine N-oxide VII do. 6 mg 133S-(Lp-butoxybenzamidoethyl)mercapto acetic acid I or IV do. 6 mg 1342-t-butylthio ethylamine hydrochloride Ill do. 6 mg 1352-methoxycarbonyl methylthio ethylamine hydrochloride V do. 6 mg 1362-ethoxycarbonylmethylthio ethylamine I hydrochloride V do. 10 mg 1372-propoxycarbonylmcthyl thio ethylaminc hydrochloride V do. 10 mg 1382-butoxycarbonylmethylthio ethylamine hydrochloride V do. 10 mg 1392,2'-thio diethylamine dihydrochloride I or IV do. 10 mg 1403-(Z-aminoethylthio)alanine hydrochloride l or IV do. 10 mg 141Z-bcnzylthio ethylammonium diacid phosphate I or IV do. 12.5 mg 142Z-methylthio ethylamine I or IV do. 12.5 mg 143 N-(methylthioethyl)p-acetamidobenzamide VII or IV do. 12.5 mg 144N-(2-methylthioethyl)nicotinamide do. do. 12.5 mg 145N-(Z-methylthioethyl)benzamide do. do. 15 mg 146 N-(Z-methylthioethyl)p-methoxybenzamidc do. do. 15 mg 147 N-(-2-methylthioethyl)p-butoxybenzamide do. do. 15 mg 148 N-(Z-methylthioethyl) butyramide do.do. 15 mg 149 N-(Z-methylthioethyl) propionamide do. do. 15 mg 150N-(Z-methylthioethyl) acetamide do. do. 17.5 mg 151N-(Z-methylthioethyl) butanesulfonamide do. do. 17.5 mg 152N-(Z-octylthioethyl) methanesulfonamide do. do. 17.5 mg 153 Z-cetylthioethylamine hydrochloride I y do. 175 mg 154 2-(2-hydroxyethylthio)ethylamine hydrochloride I or IV do. 17.5 mg 155 2-methylthio ethylaminephenylucetate l or IV do. 20 mg 156 Z-methylthio ethylamine undecylenateI or IV do. 20 mg What is claimed is: 3-methylthio alanine hydrochlorideand 1. A method for treating a scalp. characterized by an 45Q-(B-ureidoethylthio) alanine, excessive secretion of sebum, to improvethe condition said active compound being present in amounts rangingthereof by reducing said excessive secretion of sebum from 0.75 to 3percent by weight of said composition comprising orally administering toa human being havand said composition being administered at a rate of mga scalp so characterized a therapeutic composition l-5 mg/kg/day basedon the weight of the human becomprising an ingestible carrier admixedwith a noning. toxic active compound selected from the group consist- 502. The method of claim 1 wherein said non-toxic acmg f I tive compoundis 3-(B-ureidoethylthio) alanine.

3-a1lylthio alanine hydrochloride,

UNITED STATES @WICE MRTIFIQATE 0F CURRECTION Patent No, 3,821,405 DatedJune 28, 1974 Inventor(s) Gregoire Kalopissis and Georges Manoussos Itie certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In the headings:

Add the following:

-- [30] Foreign Application Priority Data February 21, 1967 Luxembourg53029- February 20, 1968 Luxembourg 55522 April 23, 1971 Luxembourg63056 April 23, 1971 Luxembourg 63057-- Col. 18 line 34, should read:

line 55, the structural formula at the left should read:

CH OH jcH Signed and sealed this 5th day of November 1974 (S Attest:

f MCCOY M. GIBSON JR. c. MARSHALL DANN Attesting Officer Commissioner ofPatents ORM PC4050 (10-69)

2. The method of claim 1 wherein said non-toxic active compound is 3-(Beta -ureidoethylthio) alanine.